The proposed studies are designed to advance our knowledge of acid-based physiology and pathophysiology in humans, with particular reference to renal regulation of plasma acid-base composition in healthy persons and in patients with renal and adrenal dysfunction. We propose: (a) to ascertain in humans whether the normal renal defense against metabolic acidosis during a sustained increase in systemic acid load is dependent on the increased adrenal secretion of aldosterone known to occur and persist under these conditions; (b) to determine in humans whether normal circulating levels of aldosterone, as modulated by normal variations in dietary sodium, chloride and potassium, exert a tonic stimulatory effect on renal acidification sufficient in magnitude to influence the "set-point" at which the kidneys regulate plasma biocarbonate concentration; (c) to test the hypothesis that renal hyperchloremic acidosis and hyperkalemia in some patients with chronic renal insufficiency results in part from abnormally increased reabsorption of chloride by the renal tubule; (d) to ascertain whether hyperkalemia per se (or increased body potassium) is a significant acidosis-producing factor in patients with chronic renal insufficiency of diverse etiology, and to characterize the renal and extrarenal mechanisms involved; (e) to investigate in humans the pathophysiology of an experimental model of chronic distal renal tubular acidosis induced by administration of amiloride; (f) to ascertain in humans whether the normal renal defense against metabolic alkalosis of extrarenal origin that results dietary potassium depletion is dependent on the reduced levels aldosterone that occur under these conditions; (g) to quantify the alterations in plasma and urine acid-based composition that occur during chronic hypocapnia in humans, and to determine the renal and extrarenal adaptive mechanisms; (h) to investigate the chronic systemic and renal acid-based effects of hypophosphaturia and dietary phosphate depletion in normal subjects with and without a sustained increase in systemic acid load; (i) to characterize the acidification dysfunction in familial (autosomal dominant) distal renal tubular acidosis, and in Sjogren's syndrome; (j) to investigate the pathophysiology of a unique, familial, nephrocalcinotic variant of Bartter's syndrome without impaired renal diluting ability.